Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain

Department of Psychiatry, Columbia University, New York, New York, United States
Human Molecular Genetics (Impact Factor: 6.68). 06/2007; 16(10):1133-42. DOI: 10.1093/hmg/ddm054
Source: PubMed

ABSTRACT Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.

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Available from: Louis Dubeau, Aug 20, 2015
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    • "[24] [25] [26] [27]). Expansions have been observed in non-dividing cells in affected humans including neurons of patients with Huntington disease (HD) [28] [29], Dentatorubral–pallidoluysian atrophy (DRPLA) [30] and Friedreich ataxia (FRDA) [31]. Expansions are also seen in the oocytes of women with myotonic dystrophy type 1 (DM1) [32] [33] and a maternal age effect is seen on the transmission of expanded alleles in DM1, fragile X syndrome (FXS) and FRDA [13] [34] [35]. "
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    ABSTRACT: DNA repair normally protects the genome against mutations that threaten genome integrity and thus cell viability. However, growing evidence suggests that in the case of the Repeat Expansion Diseases, disorders that result from an increase in the size of a disease-specific microsatellite, the disease-causing mutation is actually the result of aberrant DNA repair. A variety of proteins from different DNA repair pathways have thus far been implicated in this process. This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion. Published by Elsevier B.V.
    DNA repair 04/2015; DOI:10.1016/j.dnarep.2015.04.019 · 3.36 Impact Factor
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    • "To assess RTEL1 and Fbh1 activity toward expansions , we combined small interfering RNA (siRNA) treatment with a previously described TNR expansion assay (Experimental Procedures; Figure S1). A human astrocytic cell line, SVG-A, was used because these cells support expansions in culture (Debacker et al., 2012; Gannon et al., 2012) and because in vivo expansions occur in glia (Shelbourne et al., 2007). Knockdown of Fbh1 in SVG-A cells produced virtually no change (<8%) in expansion frequencies (Figure 1A). "
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    ABSTRACT: Human RTEL1 is an essential, multifunctional helicase that maintains telomeres, regulates homologous recombination, and helps prevent bone marrow failure. Here, we show that RTEL1 also blocks trinucleotide repeat expansions, the causal mutation for 17 neurological diseases. Increased expansion frequencies of (CTG⋅CAG) repeats occurred in human cells following knockdown of RTEL1, but not the alternative helicase Fbh1, and purified RTEL1 efficiently unwound triplet repeat hairpins in vitro. The expansion-blocking activity of RTEL1 also required Rad18 and HLTF, homologs of yeast Rad18 and Rad5. These findings are reminiscent of budding yeast Srs2, which inhibits expansions, unwinds hairpins, and prevents triplet-repeat-induced chromosome fragility. Accordingly, we found expansions and fragility were suppressed in yeast srs2 mutants expressing RTEL1, but not Fbh1. We propose that RTEL1 serves as a human analog of Srs2 to inhibit (CTG⋅CAG) repeat expansions and fragility, likely by unwinding problematic hairpins.
    Cell Reports 02/2014; 6(5). DOI:10.1016/j.celrep.2014.01.034 · 8.36 Impact Factor
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    • "Further, agedependent instability of Htt was observed in the striatum and the cerebral cortex of knock-in HD mice (Ishiguro et al. 2001, Kennedy & Shelbourne 2000). These findings led to the proposal that increased instability of Htt's CAG expansion might contribute to the marked vulnerability of striatal neurons in HD (Shelbourne et al. 2007). However, greater instability of CAG repeats in the striatum was also observed in other polyQ-expansion diseases displaying little or no striatal pathology (Lopes-Cendes et al. 1996, Watase et al. 2003). "
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    ABSTRACT: Abnormal expansion of a polyglutamine tract in huntingtin (Htt) protein results in Huntington's disease (HD), an autosomal dominant neurodegenerative disorder involving progressive loss of motor and cognitive function. Contrasting with the ubiquitous tissue expression of polyglutamine-expanded Htt, HD pathology is characterized by the increased vulnerability of specific neuronal populations within the striatum and the cerebral cortex. Morphological, biochemical, and functional characteristics of neurons affected in HD that might render these cells more vulnerable to the toxic effects of polyglutamine-Htt are covered in this review. The differential vulnerability of neurons observed in HD is discussed in the context of various major pathogenic mechanisms proposed to date, and in line with evidence showing a 'dying-back' pattern of degeneration in affected neuronal populations.
    Journal of Neurochemistry 03/2010; 113(5):1073-91. DOI:10.1111/j.1471-4159.2010.06672.x · 4.24 Impact Factor
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